Spiro epoxides as intermediates

ABSTRACT

The present invention provides compounds of formula (I) wherein the substituents are as defined in claim  1.  The compounds are suitable intermediates in the preparation of herbicidally active 4-phenyl-3,5-pyrandiones, 4-phenyl-3,5-thiopyran-diones and 6-phenylcyclohexane-1,3,5-triones.

The present invention relates to novel compounds, their preparation andtheir use as intermediates in the preparation of herbicidally activesubstituted 4-phenyl-3,5-pyrandiones, 4-phenyl-3,5-thiopyrandiones and6-phenylcyclohexane-1,3,5-triones.

4-Phenyl-3,5-pyrandiones, 4-phenyl-3,5-thiopyrandiones and6-phenylcyclohexane-1,3,5-triones having herbicidal action and a processfor the preparation of these compounds are described, for example, in WO08/071405.

It has now been discovered that certain substituted epoxyketones can beused as key intermediates in the process for preparing such herbicidallyactive diones and triones. These are now obtainable in high yield andwith considerable advantages over the known processes.

The present invention accordingly relates to compounds of formula I

-   -   wherein    -   R¹ is halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₃-C₆cycloalkyl,        C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkylthio,        C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl;    -   R² is hydrogen, halogen, methylsulfonyloxy,        C₁-C₄haloalkylsulfonyloxy, p-tolylsulfonyloxy, optionally        substituted aryl or optionally substituted heteroaryl;    -   r is 0, 1, 2 or 3;    -   R³, if r is 1, is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy,        C₁-C₆haloalkoxy, C₁-C₆alkylthio, C₁-C₆alkylsulfinyl,        C₁-C₆alkylsulfonyl, cyano or nitro; or the substituents R³, if r        is 2 or 3, independently of each other, are C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₁-C₆alkylthio,        C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, cyano or nitro;    -   Y is O, S, SO, SO₂ or CO;    -   R⁴, R⁵, R⁶ and R⁷, independently of each other, are hydrogen,        C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxyC₁-C₄alkyl,        C₁-C₄alkylthioC₁-C₄alkyl, C₁-C₄alkylsulfinylC₁-C₄alkyl,        C₁-C₄alkylsulfonylC₁-C₄alkyl, cyclopropyl or cyclopropyl        substituted by C₁- or C₂alkyl, C₁- or C₂haloalkyl or halogen;        cyclobutyl or cyclobutyl substituted by C₁- or C₂alkyl; oxetanyl        or oxetanyl substituted by C₁- or C₂alkyl; C₅-C₇cycloalkyl or        C₅-C₇cycloalkyl substituted by C₁- or C₂alkyl or C₁- or        C₂haloalkyl, where a methylene group of the cycloalkyl moiety is        optionally replaced by an oxygen or sulfur atom or a sulfinyl or        sulfonyl group; C₄-C₇cycloalkenyl or C₄-C₇cycloalkenyl        substituted by C₁- or C₂alkyl or C₁- or C₂haloalkyl, where a        methylene group of the cycloalkenyl moiety is optionally        replaced by an oxygen or sulfur atom or a sulfinyl or sulfonyl        group; cyclopropylC₁-C₅alkyl or cyclopropylC₁-C₅alkyl        substituted by C₁- or C₂alkyl, C₁- or C₂haloalkyl or halogen;        cyclobutylC₁-C₅alkyl or cyclobutylC₁-C₅alkyl substituted by C₁-        or C₂alkyl; oxetanylC₁-C₅alkyl or oxetanylC₁-C₅alkyl substituted        by C₁- or C₂alkyl; C₅-C₇ cycloalkylC₁-C₅alkyl or        C₅-C₇cycloalkylC₁-C₅alkyl substituted by C₁-or C₂alkyl or C₁- or        C₂haloalkyl, where a methylene group of the cycloalkyl moiety is        optionally replaced by an oxygen or sulfur atom or a sulfinyl or        sulfonyl group; C₄-C₇cycloalkenylC₁-C₅ alkyl or        C₄-C₇cycloalkenylC₁-C₅alkyl which is substituted by C₁- or        C₂alkyl or C₁- or C₂haloalkyl, where a methylene group of the        cycloalkenyl moiety is optionally replaced by an oxygen or        sulfur atom or a sulfinyl or sulfonyl group; phenyl or phenyl        substituted by C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, halogen,        nitro, cyano, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl,        C₁-C₄alkylsulfonyl or C₁-C₄alkylcarbonyl; benzyl or benzyl        substituted by C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, halogen,        nitro, cyano, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl,        C₁-C₄alkylsulfonyl or C₁-C₄alkylcarbonyl; heteroaryl or        heteroaryl substituted by C₁-C₄alkyl, C₁-C₄alkoxy,        C₁-C₄haloalkyl, halogen, nitro, cyano, C₁-C₄alkylthio,        C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl or C₁-C₄alkylcarbonyl; or        R⁴ and R⁵, or R⁶ and R⁷, are joined to form a 5-7 membered        saturated or unsaturated ring in which a methylene group is        optionally replaced by an oxygen or sulfur atom, or a 5-7        membered saturated or unsaturated ring substituted by C₁- or        C₂alkyl, where a methylene group of the ring is optionally        replaced by an oxygen or sulfur atom; or    -   R⁴ and R⁷ are joined to form a 5-7 membered saturated or        unsaturated ring unsubstituted or substituted by C₁- or C₂alkyl,        C₁- or C₂alkoxy, C₁- or C₂alkoxyC₁- or C₂alkyl, hydroxy,        halogen, phenyl or phenyl substituted by C₁-C₄alkyl,        C₁-C₄alkoxy, C₁-C₄haloalkyl, halogen, nitro, cyano,        C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl or        C₁-C₄alkylcarbonyl; heteroaryl or heteroaryl substituted by        C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, halogen, nitro, cyano,        C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl or        C₁-C₄alkylcarbonyl.

The present invention also relates to a new process for the preparationof the compounds of formula I.

The invention further relates to a process for the preparation of4-phenyl-3,5-pyrandiones, 4-phenyl-3,5-thiopyrandiones and6-phenylcyclohexane-1,3,5-triones of formula (A) which is shown below,using the compounds of the formula I as intermediates.

In the substituent definitions of the compounds of the formula I, thealkyl substituents and (halo)alkyl moieties of alkoxy, alkylthio etc.having 1 to 6 carbon atoms are preferably methyl, ethyl, propyl, butyl,pentyl and hexyl, in the form of their straight and branched isomers.Suitable cycloalkyl groups contain 3 to 7 carbon atoms and are forexample cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl arepreferred. Suitable cycloalkene groups contain 4 to 7 carbon atoms andmay contain up to 3 double bonds. Preferred halogens are fluorine,chlorine and bromine. Preferred examples of aryls are phenyl andnaphthyl. Preferred examples of heteroaryls are thienyl, furyl,pyrrolyl, isoxazolyl, oxazolyl, oxetanyl, isothiazolyl, thiazolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyrazinyl, triazinyl, oxadiazolyl, thiadiazolyl and pyridazinyl, and,where appropriate, N-oxides and salts thereof. These aryls andheteroaryls can be substituted by one or more substituents, wherepreferred substituents are halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₂-C₄alkenyl, C₂-C₄haloalkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl,C₁-C₄haloalkylthio, C₁-C₄haloalkylsulfinyl, C₁-C₄haloalkylsulfonyl,nitro or cyano.

In a preferred group of compounds of formula I, R¹ is halogen,C₁-C₄alkyl, C₁-C₄haloalkyl, C₃-C₆cycloalkyl or C,C₄-haloalkoxy.

In another preferred group of compounds of formula I, R² is halogen,aryl or heteroaryl; or aryl or heteroaryl both substituted by halogen,C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₄alkenyl, C₂-C₄haloalkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, phenoxy, C₁-C₄alkylthio,C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl, C₁-C₄haloalkylthio,C₁-C₄haloalkylsulfinyl, C₁-C₄haloalkylsulfonyl, C₃-C₆cycloalkyl,C₁-C₄alkylsulfonyloxy, C₁-C₄haloalkylsulfonyloxy, C₁-C₄alkoxyC₁-C₄alkyl,C₁-C₄alkylthioC₁-C₄alkyl, C₁-C₄alkylsulfinylC₁-C₄alkyl,C₁-C₄alkylsulfonylC₁-C₄alkyl, nitro, cyano, thiocyanato, hydroxy, amino,C₁-C₆alkylamino, C₁-C₆dialkylamino, C₃-C₆cycloalkylamino, morpholino,thiomorpholino, C₁-C₆alkylcarbonylamino, C₁-C₆alkoxycarbonylamino, C₃-C₆alkenyloxycarbonylamino, C₃-C₆ alkynyloxycarbonylamino, C₁-C₆alkylaminocarbonylamino, di(C₁₋₆alkyl)aminocarbonylamino, formyl,C₁-C₆alkyl-carbonyl, C₂-C₆alkenylcarbonyl, C₂-C₆alkynylcarbonyl,carboxy, C₁-C₆alkoxycarbonyl, C₃-C₆alkenyloxycarbonyl,C₃-C₆alkynyloxycarbonyl, carboxamido, C₁-C₆alkylaminocarbonyl,di(C₁-C₆alkyl)aminocarbonyl, C₁-C₆alkylcarbonyloxy,C₁-C₆alkylaminocarbonyloxy, di(C₁-C₆alkyl)aminocarbonyloxy orC₁-C₆alkylthiocarbonylamino.

Preferably, R² in the compounds of formula I is halogen, aryl orheteroaryl; or aryl or heteroaryl both substituted by halogen,C₁-C₄alkyl, C₁-C₄haloalkyl, phenoxy, C₂-C₄alkenyl, C₂-C₄haloalkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkylthio,C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl, C₁-C₄haloalkylthio,C₁-C₄haloalkylsulfinyl, C₁-C₄haloalkylsulfonyl, nitro or cyano.

More preferably, R² is phenyl, thienyl, furyl, pyrrolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, pyridazinyl,oxadiazolyl and thiadiazolyl, and N-oxides and salts thereof, wherethese rings are unsubstituted or substituted by halogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₂-C₄alkenyl, C₂-C₄haloalkenyl, C₂-C₄alkynyl,C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl,C₁-C₄alkylsulfonyl, C₁-C₄haloalkylthio, C₁-C₄haloalkylsulfinyl,C₁-C₄haloalkylsulfonyl, nitro or cyano.

In even more preferred compounds of the formula I, R² is phenyl orpyridyl or phenyl or pyridyl both substituted by halogen, nitro, cyano,C₁-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂alkoxy or C₁-C₂haloalkoxy.

In an especially preferred group of compounds, R² is phenyl substitutedat the para-position by halogen (in particular chlorine) and isoptionally further substituted by halogen, nitro, C₁ C₂alkyl,C₁-C₂haloalkyl, C₁-C₂alkoxy or C₁-C₂haloalkoxy.

Preferably, R³ is hydrogen (r is 0) or C₁-C₆alkyl, especially hydrogen.

Preferably, R³, if r is 1, is C₁-C₃alkyl.

Preferred are those compounds of the formula I, wherein R⁴, R⁵, R⁶ andR⁷, independently of each other, are hydrogen, C₁-C₄alkyl,C₁-C₄haloalkyl, C₁-C₄alkoxyC₁-C₄alkyl, C₁-C₄alkylthioC₁-C₄alkyl,C₁-C₄alkylsulfinylC₁-C₄alkyl, C₁-C₄alkylsulfonylC₁-C₄alkyl;C₅-C₇cycloalkyl or C₅-C₇cycloalkyl substituted by C₁- or C₂alkyl or C₁-or C₂haloalkyl and in which a methylene group is optionally replaced byan oxygen or sulfur atom or a sulfinyl or sulfonyl group;C₅-C₇cycloalkylC₁-C₅alkyl or C₅-C₇cycloalkylC₁-C₅alkyl substituted byC₁-C₂alkyl or C₁- or C₂haloalkyl and in which a methylene group isoptionally replaced by an oxygen or sulfur atom or a sulfinyl orsulfonyl group.

More preferably, R⁴, R⁵, R⁶ and R⁷, independently of each other, arehydrogen, C₁-C₂alkyl, C₁-C₂haloalkyl or C₁-C₂alkoxyC₁-C₂alkyl.

In a preferred group of compounds of the formula (I), R¹ is ethyl,methyl or cyclopropyl, R² is phenyl or phenyl substituted by halogen orC₁-C₂alkyl, R³ is hydrogen, R⁴, R⁵, R⁶ and R⁷, independently of eachother, are C₁-C₂alkyl.

In another preferred group of compounds of the formula (I), R₁ ismethyl, ethyl, cyclopropyl, n-propyl, halogen, trifluoromethoxy,difluoromethoxy and trifluoromethyl, R₄, R₅, R₆ and R₇, independently ofeach other, are hydrogen, methyl and ethyl, R₂ is halogen, phenylsubstituted by halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄haloalkoxy orC₁-C₄alkoxy, R₃ is hydrogen and Y is oxygen, where

more preferably, R₁ is ethyl or cyclopropyl, R₄, R₅, R₆ and R₇ aremethyl, R₂ is phenyl substituted once or twice by fluorine, chlorine,methoxy or methyl, R₃ is hydrogen and Y is oxygen, where

most preferably, R₁ is ethyl, R₄, R₅, R₆ and Rare methyl, R₂ is4-chlorophenyl, 2,4-dichlorophenyl and 2-fluoro-4-chlorophenyl, R₃ ishydrogen and Y is oxygen.

In another preferred group of compounds of the formula (I), R₁ is ethyl,trifluoromethyl, cyclopropyl, difluoromethoxy, trifluoromethoxy, fluoro,bromine or iodine, R₄, R₅, R₆ and R₇, independently of each other, arehydrogen or methyl, R₂ is bromine, 4-chlorophenyl,2-fluoro-4-chlorophenyl, 2,4-di-chlorophenyl, R₃ is hydrogen and Y is O,where more preferably, R₁ is ethyl, cyclopropyl, R₄, R₅, R₆ and R₇ aremethyl, R₂ is bromine, 4-chlorophenyl, 2-fluoro-4-chlorophenyl or2,4-di-chlorophenyl, R₃ is H and Y is O.

In a further aspect of the invention, it has now been found,surprisingly, that the compounds of formula I can easily be convertedinto 4-phenyl-3,5-pyrandiones, 4-phenyl-3,5-thio-pyrandiones and6-phenylcyclohexane-1,3,5-triones of formula (A) below in the presenceof an acid.

Suitable acids include Brönsted acids such as mineral acids and organicacids, for example sulfuric acid, hydrochloric acid, hydrogen chloride,p-toluenesulfonic acid, acetic acid and formic acid, and Lewis acidssuch as metal halides, for example boron trifluoride, aluminiumchloride, iron chloride, tin(IV) chloride, zinc chloride, zinc bromide,lithium perchlorate, as well as metal triflates such as scandiumtriflate and ytterbium triflate. Mixtures of such acids can also beused. The conversion of a compound of formula (I) into a compound offormula (A) may be considered to be an example of a semi-Pinacolrearrangement (see for example M. Paulson, M. Daliya and C. Asokan,Synth. Commun. (2007), 37(5), 661-665; S. Sankararaman and J. Nesakumar,J. Chem. Soc. Perkin Trans. 1, (1999), (21), 3173-3175; K. Rehse and R.Bienfait, Archiv der Pharmazie, (1984), 317(5), 385-93; H. Kamath, A.Sahasrabudhe, B. Bapat and S. Kulkarni, Indian J. Chem., Section B:(1981), 20B(12), 1094-6; G. Buchanan and D. Jhaveri, J. Org. Chem.(1961), 26 4295-9; and H. House, Richard L. Wasson, J. Am. Chem. Soc.,(1956), 78, 4394-400), but such a transformation is unknown forcompounds of type (I). The reactions conditions which are useful in theprocess of the present invention are similar to those described in theliterature mentioned above or can be derived by those skilled in theart. Suitable solvents are those chosen to be compatible with the acidused, and include chlorinated hydrocarbons, alcohols, ethers, aromaticsand organic acids, for example dichloromethane, dichloroethane, diethylether, acetic acid, formic acid, toluene, benzene, methanol, ethanol,isopropanol and tetrahydrofuran. Mixtures of solvents can also be used.Preferably the reaction is performed using concentrated sulphuric acidin dichloroethane. The preferred reaction temperature is within therange of between −50° C. and 83° C., even more preferably between −50°C. and 40° C. Additional preferred reaction conditions are the use oflithium perchlorate solution in ether in combination with 0.1-100 mol %ytterbium triflate as acid, at a temperature range between 0° C. and 60°C.

The present process is distinguished over the art mentioned above by:

(a) easy accessibility of the starting materials,

(b) a short reaction sequence,

(c) avoidance of highly toxic reagents

(d) high volume concentration of the reactants (demonstrated up to 20%,example P1 step 4).

(e) widely—especially in the 2 and 5 positions—substituted phenylderivatives as starting compounds,

(f) generally high product yields, and

(g) economic and ecological advantages derived from the fact that theprocess can be used as a partial step in a continuous reaction procedurefor the preparation of 4-phenyl-3,5-pyrandiones,4-phenyl-3,5-thiopyrandiones and 6-phenylcyclohexane-1,3,5-triones offormula (A), which are known to exhibit herbicidal properties.

The present preparation process is therefore suitable especially for thecost-effective, large-scale preparation of the diones and triones offormula (A).

The compounds of formula (I), and this is another aspect of the presentinvention, can be obtained by the epoxidation of compounds of formula(B), as is illustrated in the following reaction scheme:

wherein Y, R¹, R², R³, r, R⁴, R⁵, R⁶ and R⁷ are as defined above. Thecompounds of the formula (B) are novel and have been especially designedas intermediates for the synthesis of the compounds of formula (I) andform another aspect of the invention.

Epoxidation may be effected by treatment of a compound of formula (B)with a suitable oxidising agent such as an organic peroxide or metalhyperchlorite, for example dimethyldioxirane, sodium hypochlorite,hydrogen peroxide, tert-butyl peroxide or trifluoroperacetic acid,optionally in combination with a suitable base (such as an alkali metalhydroxide or carbonate, alkaline earth metal hydroxide or carbonate, oran amine base such as 1,8-diazabicyclo[5.4.0]-undec-7-ene), optionallyin a suitable solvent (such as an alcohol, a halogenated hydrocarbon oran aromatic compound, for example methanol, ethanol, dichloromethane ortoluene) and at a suitable temperature. The reaction can also beperformed under biphasic conditions, in which a phase-transfer reagentis also typically used in 0.001-50 mol %. The phase transfer reagent ispreferably a quaternary ammonium salt, a crown ether, a polyethyleneglycol, or phosphonium salt and at a suitable temperature. Similarreactions are known in the literature (see for example, I. K.Korobitsyna, O. P. Studzinskii, The Russian Journal of Organic Chemistry(1969), 5(8), 1493-5; A. Halasz, Z. Jambor, A. Levai, C. Nemes, T.Patonay and G. Toth, J. Chem. Soc, Perkin Trans. 1, (1996), (4),395-400; N. Yousif, F. Gad, A. Fahmy, M. Amine and H. Sayed, Phosphorus,Sulfur and Silicon and the Related Elements (1996), 117, 11-19; T. Ooi,D. Ohara, M. Tamura and K. Maruoka, J. Am. Chem. Soc., (2004), 126(22),6844-6845; A. Amr, H. Hayam and M. Abdulla, Archiv der Pharmazie,(2005), 338(9), 433-440; K. Drauz, S. M. Roberts, T. Geller and A.Dhanda, U.S. Pat. No. 6,538,105 B1; and L. S. Chagonda and B. A.Marples, J. Chem. Soc. Perkin 1, 1988, 875-879). Mixtures of oxidisingagents, bases, and solvents can also be used. Preferably, epoxidation iscarried out using hydrogen peroxide and a metal hydroxide (especiallylithium hydroxide or sodium hydroxide), in methanol at a temperature ofbetween −10° C. and 60° C.

A compound of formula (B) may be prepared from a compound of formula (C)by condensation with a benzaldehyde of formula (D), in the presence of asuitable base and optionally in the presence of a suitable solvent (seefor example, A. Lagrange, S. Forestier, G. Lang and B. Luppi, EP368717A1; D. C. Rowlands, U.S. Pat. No. 2,776,239; and E. Tamate, Journal ofthe Chemical Society of Japan, (1957), 78, 1293-7).

Preferably the base is a metal hydroxide, such as sodium hydroxide orpotassium hydroxide, or a metal alkoxide such as sodium methoxide,sodium ethoxide or potassium tert-butoxide. Preferably the solvent isdimethoxyethane, dioxane, tetrahydrofuran, diethyl ether or an alkylalcohol, such as methanol, ethanol or isopropanol. Mixtures of basesand, in particular, solvents can also be used.

Compounds of formula (C), wherein Y is O, are known compounds (see forexample M. Newman and W. Reichle, Org. Synth. Coll. Vol. V., (1973),1024; Y. Zal'kind, E. Venus-Danilova and V. Ryabtseva, Russian Journalof General Chemistry, (1950), 20, 2222-9; M. Bertrand, J. Dulcere, G.Gil, J. Grimaldi and P. Sylvestre-Panthet, Tetrahedron Letters (1976),(18), 1507-8), or may be prepared from known compounds by known methods.Compounds of formula (C), wherein Y is C═O, are known compounds (see forexample N. J. Turro, D. R. Morton, E. Hedaya, M. E. Kent, P. D'Angelo,P. Schissel, Tetrahedron Letters (1971), (27), 2535-8; P. A. Krapcho, D.R. Rao, M. P. Silvon, B. Abegaz, Journal of Organic Chemistry (1971),36(25), 3885-90; S. N. Crane, T. J. Jenkins, D. J. Burnell, Journal ofOrganic Chemistry (1997), 62(25), 8722-8729; S. N. Crane, D. J. Burnell,Journal of Organic Chemistry (1998), 63(4), 1352-1355; S. N. Crane, D.J. Burnell, Journal of Organic Chemistry (1998), 63(16), 5708-5710; C.E. Elliott, D. O. Miller, D. J. Burnell, Journal of the ChemicalSociety, Perkin Transactions 1 (2002), (2), 217-226), or may be preparedfrom known compounds by known methods. Compounds of formula (C), whereinY is S, SO or SO₂ are known compounds (see for example E. R. Buchman, H.Cohen, Journal of the American Chemical Society (1944), 66, 847-8; A. W.D. Avison, F. Bergel, J. W. Haworth, U.S. Pat. No. 2,408,519: K. G.Mason, M. A. Smith, E. S. Stern, E J. A. Elvidge, Journal of theChemical Society [Section] C: Organic (1967), (21), 2171-6; T. A. Magee,Thomas A. DE 2033454; I. Tabushi, Y. Tamaru, Z. Yoshida, T. Sugimoto,Journal of the American Chemical Society (1975), 97(10), 2886-91; P. E.Aldrich, G. H. Berezin, B. I. Dittmar, I. Bruce, DE 2516554; I. Tabushi,Y. Tamaru, Z. Yoshida, Bulletin of the Chemical Society of Japan (1978),51(4), 1178-82; D. N. Reinhoudt, J. Geevers, W. P. Trompenaars, S.Harkema, G. J. Van Hummel, Journal of Organic Chemistry (1981), 46(2),424-34; F. Duus, Synthesis (1985), (6-7), 672-4; J. Schatz, Science ofSynthesis (2002), 9, 287-422), or may be prepared from known compoundsby known methods.

Compounds of formula (D) are either known compounds, or can be preparedby formylation of a compound of formula (E) wherein Hal is chlorine,bromine or iodine (preferably bromine or iodine).

wherein R¹, R², R³ and r and Hal is halogen as defined above. Preferredcompounds of the formula (D) are the compounds of the formula (D1)

wherein R¹, R³ and r as defined above and R²⁰ and R³⁰, independently ofeach other, are hydrogen, methyl, methoxy, fluorine, chlorine orbromine. The compounds of the formula (D) as far as they are novel andthe novel compounds of the formula (D1) have been especially designed asintermediates for the synthesis of the compounds of formula (I) and formanother aspect of the invention.

Suitable conditions for effecting the formylation of aryl halides areknown, and include, for example, the treatment of an aryl halide with asuitable organometallic reagent (such as isopropyl magnesium chloride,n-butyllithium, sec-butyllithium or tert-butyllithium), or by treatmentwith a suitable alkali metal or alkali earth metal (such as lithium ormagnesium) in a suitable solvent (such as diethyl ether, dimethoxyethaneor tetrahydrofuran). The resulting arylmetal reagent is then reactedwith a suitable formylating agent such as N,N-dimethylformamide orN-formylmorpholine. Alternatively a compound of formula (D) may beprepared from a compound of formula (E) (wherein Hal can also be apseudohalogen such as triflate) by treatment with a carbonylating agent(such as carbon monoxide) in the presence of a suitable catalyst, base,and reducing agent (see for example L. Ashfield and C. Barnard, Org.Process Res. Dev., 11 (1), 39-43, 2007). Compounds of formula (E) areeither known compounds (see for example WO 2008/071405), or may besynthesised from known intermediates using standard chemicaltransformations.

Alternatively a compound of formula (I) may be prepared by reacting acompound of formula (F) (wherein halogen is chlorine, bromine or iodine,preferably chlorine or bromine) with a compound of formula (D), asillustrated in the following reaction scheme.

The reaction of (F) and (D) can be performed with a suitable base,optionally in a suitable solvent, at a suitable temperature. Preferablythe base is an alkali or alkali earth metal hydroxide (such as sodiumhydroxide, lithium hydroxide or potassium hydroxide), an alkali oralkali earth metal alkoxide (such as sodium methoxide, sodium ethoxideor potassium tert-butoxide), an alkali or alkali earth metal carbonate(such as potassium carbonate or sodium carbonate, or sodiumbicarbonate), a metal amide (such as lithium diisopropylamide, lithiumhexamethyldisilazide or lithium 2,2,6,6-tetramethylpiperidide), anorganometallic (such as butyl lithium or ethylmagnesium bromide) or ametal hydride (such as sodium hydride or potassium hydride). Suitablesolvents include chlorinated hydrocarbons, ethers, alcohols, aromaticsand various polar aprotic solvents, for example 1,2-dimethoxyethane,tetrahydrofuran, 1,4-dioxane, diethyl ether, dibutyl ether,dichloromethane, dichloroethane, acetonitrile, dimethyl sulfoxide,benzene, toluene, methanol, ethanol, isopropanol or tert-butanol, and ischosen to be compatible with the base under the reaction conditions. Thereaction can also be performed under biphasic conditions, in which aphase-transfer reagent is also typically used in 0.001-50 mol %. Thephase transfer reagent is preferably a quaternary ammonium salt, a crownether, a polyethylene glycol, or phosphonium salt. Most preferably thereaction is performed using lithium diisopropylamide in tetrahydrofuranat a temperature range of −100° C. to 60° C. The conversion of acompound of formula (F) into a compound of formula (I) may be consideredto be an example of a Darzens condensation (see for example, W. N.Wassef, M. M. El-Barky, Journal of Chemical Research, Synopses (1990),(12), 402-3; J. Li, X. Liu, X. Li, Youji Huaxue (2007), 27(11),1428-1431; Y. Tong, Y. Cheng, X. Guo, S. Wu, Hecheng Huaxue (2007),15(1), 102-104; C. Parmenon, J. Guillard, D. Caignard, N. Hennuyer, B.Staels, V. Audinot-Bouchez, J. Boutin, C. Dacquet, A. Ktorza, M.Viaud-Massuard, Bioorganic & Medicinal Chemistry Letters (2008), 18(5),1617-1622; H. Xiao, X. Han, J. Xiong, Faming Zhuanli Shenqing GongkaiShuomingshu (2007), p 11; J. M. Concellon, E. Bardales, R. Llavona,Journal of Organic Chemistry (2003), 68(4), 1585-1588), but such atransformation is unknown for compounds of type (F).

Compounds of formula (F), wherein Y is O, are either known compounds(see for example H. Richet, R. Dulou, R., G. Dupont, Bulletin de laSociete Chimique de France (1947), 693-9; H. Richet, Ann. Chim. [12](1948), 3 317-54; I. K. Korobitsyna, Yu. K. Yur'ev, Yu. A. Cheburkov, E.M. Lukina, Russian Journal of General Chemistry (1955), 25, 734-8; I. K.Korobitsyna, Yu. K. Yur'ev, Yu. A. Cheburkov, E. M. Lukina, RussianJournal of General Chemistry (1955), 25, 690-702; F. Leonard, A.Wajngurt, H. Horn, Journal of Organic Chemistry (1956), 21, 1400-4; I.K. Korobitsyna, I. G. Zhukova, V. A. Kuvshinova, N. N. Gaidamovich, Yu.K. Yur'ev, Doklady Akademii Nauk SSSR (1957), 114, 327-30; I. K.Korobitsyna, I. G. Zhukova, I. G, Yu. K. Yur'ev, Russian Journal ofGeneral Chemistry (1959), 29, 2190-6; I. K. Korobitsyna, L. L. Rodina,L. M. Stashkova, Chemistry of Heterocyclic Compounds (1966), (6), 843-7;G. Hoehne, F. Marschner, K. Praefcke, P. Weyerstahl, Chem. Ber. (1975),108(2), 673-82; H. Saimoto, T. Hiyama, H. Nozaki, Bull. Chem. Soc. Jpn.,(1983), 56(10), 3078-87; A. M. Zvonok, N. M. Kuz'menok, I. G.Tishchenko, L. S. Stanishevskii, Russian Journal of General Chemistry(1985), 21(6), 1330-4) or can be prepared from compounds of formula (C)under known conditions. Compounds of formula (F), wherein Y is S, SO andSO₂, are either known compounds (see for example M. Polievka, L. Uhlar,V. Patek, Petrochemia (1973), 13(5-6), 156-60; N. N. Novitskaya, B. V.Flekhter, G. M. Prokhorov, A. S. Lukmanova, G. A. Tolstikov, G. V.Leplyanin, S. A. Lange, M. V. Strashnov, SU 468920 A1; P. H. McCabe, W.Routledge, Tetrahedron Letters (1976), (1), 85-6; T. S. Chou, C. Y.Tsai, Tetrahedron Letters (1992), 33(29), 4201-4), or can be preparedfrom compounds of formula (C) under known conditions. Compounds offormula (F), wherein Y is C═O, can be prepared from compounds of formula(C) under similar halogenation conditions.

The Examples that follow further illustrate the invention withoutlimiting it.

PREPARATION EXAMPLES Example P1 Preparation of4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of 5-Bromo-2-ethyl-benzaldehyde

To a solution of 4-bromo-1-ethyl-2-iodobenzene (31.8 g, 103 mmol)(described in WO 2008/071405) in anhydrous tetrahydrofuran (250 ml) at−20° C. is added isopropyl magnesium chloride (55 ml, 110 mmol, 2Msolution in tetrahydrofuran) dropwise over 10 minutes. Once the additionis complete the reaction mixture is stirred at −20° C. for 3 hours,followed by dropwise addition of anhydrous N,N-dimethylformamide (16.0ml, 200 mmol). The reaction mixture is stirred at room temperature for afurther 2.5 hours, then left to stand overnight. 2M hydrochloric acid(90 ml) is added and the crude product is extracted intodichloromethane. Organics are combined, dried over magnesium sulfatethen filtered and the filtrate evaporated under reduced pressure toafford 5-bromo-2-ethyl-benzaldehyde (21.20 g) as an orange liquid.

Step 2: Preparation of4-(5-Bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone(13.4 g, 94.34 mmol) in anhydrous 1,2-dimethoxyethane (32 ml) is addedsodium methoxide (5.6 g, 103.8 mmol) in one portion, and the reactionmixture is stirred at this temperature for 5 minutes. To the resultingslurry is then added a solution of 5-bromo-2-ethyl-benzaldehyde (20 g,94.34 mmol) in 1,2-dimethoxyethane (32 ml) dropwise over 10 minutes. Thesolution is next stirred at 0° C. for 1 hour, then diluted with diethylether and washed with 2M hydrochloric acid (×2). Organic fractions arecombined, dried over magnesium sulphate, filtered and the filtrateevaporated in vacuo to afford4-(5-bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one(30.2 g) as a yellow liquid.

Step 3: Preparation of2-(5-Bromo-2-ethylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-(5-bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one(32.07 g, 95.15 mmol) in methanol (1570 ml) at 35° C. is added 50%aqueous hydrogen peroxide (8.10 ml, 142.73 mmol), followed immediatelyby a solution of 2M aqueous lithium hydroxide (9.51 ml, 19.03 mmol).This reaction mixture is stirred at 35° C. for exactly 1 hour, thenquenched with saturated sodium metabisulfite (340 ml) and distilledwater (340 ml). After stirring at room temperature for 15 minutessolvents are then concentrated in vacuo (to approximately 500 ml), overwhich time the product precipitates as a yellow solid. To thissuspension is added distilled water (500 ml), and the product isisolated by filtration. After additional washing with distilled waterthe solid is dried under vacuum overnight to afford2-(5-bromo-2-ethylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(29.30 g) as a yellow solid which is used without purification in thenext step.

1H NMR (CDCl₃): δ 7.47-7.40 (m, 2H), 7.10 (d, 1H), 4.43 (s, 1H),2.62-2.60 (m, 2H), 1.40 (s, 3H), 1.37 (s, 3H), 1.30-1.20 (m, 6H), 0.78(s, 3H).

Step 4: Preparation of4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione

To an ice-cold solution of concentrated sulphuric acid (2 ml) is added asecond solution of2-(5-bromo-2-ethylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(0.995 g, 2.82 mmol) in 1,2-dichloroethane (2 ml) dropwise over 5minutes. This biphasic mixture is stirred vigorously for 1 hour at 0°C., then poured into ice-cold water (15 ml). This aqueous mixture isthen concentrated under vacuum to remove all organic volatiles,producing a free-flowing solid. The solid is filtered, dried undervacuum, then washed with hexanes to afford4-(5-bromo-2-ethylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.81 g) asa cream-coloured solid.

1H NMR (CDCl₃): δ7.48 (1H, dd), 7.23-7.21 (2H, m), 5.60 (1H, s),2.45-2.33 (2H, m), 1.60 (6H, d), 1.48 (6H, d), 1.10 (3H, t).

Example P2 Preparation of4-(5-Bromo-2-ethylphenyl)-2,2,6-trimethylpyran-3,5-dione

Step 1: Preparation of 4-Bromo-2,2,5-trimethyldihydro-furan-3-one

To a solution of acetic acid4-bromo-2,2,5-trimethyl-2,5-dihydrofuran-3-yl ester (19.14 g, 0.11 mol)(described in T. Hiyama et al. Bull. Chem. Soc. Jpn., 56, 3078-3087(1983)) in anhydrous chloroform (75 ml) at −20° C. is added a solutionof bromine (18.00 g, 0.11 mol) in anhydrous chloroform (200 ml) dropwiseover 45 minutes. After stirring at this temperature for 30 minutes thereaction mixture was allowed to warm to room temperature, then furtherstirred for 1 hour. After dilution with chloroform (250 ml) the organicphase is washed with dilute aqueous sodium bicarbonate then brine, andthe phases separated. Organics solvents are removed under reducedpressure to afford 4-bromo-2,2,5-trimethyldihydro-furan-3-one (23.50 g)as a dark orange oil. This material is used without purification in thenext step.

Step 2: Preparation of2-(5-Bromo-2-ethylphenyl)-4,6,6-trimethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of lithium diisopropylamide (0.12 mol) in anhydroustetrahydrofuran (150 ml) at −70° C. is added a second solution of4-bromo-2,2,5-trimethyl-4,5-dihydro-3(2H)-furanone (23.5 g, 0.11 mol) inanhydrous tetrahydrofuran (40 ml), at such a rate as to keep theinternal temperature below −65° C. Once the addition is complete thereaction mixture is stirred at −70° C. for a further 20 minutes,followed by addition of 2-ethyl-5-bromobenzaldehyde (23.9 g, 0.11 mol)as a solution in anhydrous tetrahydrofuran (40 ml) dropwise over 20minutes. After further stirring at −70° C. for 20 minutes the reactionmixture is allowed to warm to room temperature then stirred for anadditional 30 minutes. The reaction mixture is then quenched by pouringinto ice/water (acidified to pH 3 with 2M hydrochloric acid) (500 ml)and extracted with ethyl acetate (3×100 ml). Organic fractions arecombined, washed with water and brine, then dried over magnesiumsulphate. The suspension is filtered, and the filtrate is concentratedin vacuo to afford a mixture of2-(5-bromo-2-ethylphenyl)-4,6,6-trimethyl-1,5-dioxaspiro[2.4]heptan-7-oneand 2-ethyl-5-bromobenzaldehyde (40.50 g), in an approximate 3:1 ratio.This material is used without purification in the next step.

1H NMR (CDCl₃): δ 7.47 (m, 1H), 7.41 (m, 1H), 7.10 (d, 1H), 4.47 (q,1H), 4.39 (s, 1H), 2.60 (q, 2H), 1.38 (s, 3H), 1.35 (s, 3H), 1.23 (t,3H), 0.70 (d, 3H).

Step 3: Preparation of4-(5-Bromo-2-ethylphenyl)-2,2,6-trimethylpyran-3,5-dione

To ice-cold concentrated sulphuric acid (50 ml) is added a solution ofcrude2-(5-bromo-2-ethylphenyl)-4,6,6-trimethyl-1,5-dioxaspiro[2.4]heptan-7-one(40 g) in 1,2-dichloroethane (50 ml) over 20 minutes. After furtherstirring at 0° C. for 1 hour the reaction mixture is carefully pouredinto ice (500 g), and the two phases separated. The aqueous phase isfurther extracted with dichloromethane (2×100 ml), then all organicfractions are combined, washed with water, and concentrated underreduced pressure. The crude product is re-dissolved in ethyl acetate(500 ml), extracted into 0.5M aqueous potassium carbonate, and washedwith additional ethyl acetate (×2). The aqueous phase is then carefullyacidified with concentrated hydrochloric acid, and the product extractedwith ethyl acetate (3×150 ml). Organic fractions are combined, washedwith brine then dried over magnesium sulfate, filtered, and the filtrateconcentrated in vacuo. The crude product is further purified by flashcolumn chromatography to afford4-(5-bromo-2-ethylphenyl)-2,2,6-trimethylpyran-3,5-dione (14.10 g) as awhite foam.

1H NMR (CDCl₃): δ1.08 (m, 3H), 1.38-1.62 (m, 9H), 2.25 (m, 2H), 4.38 and4.71 (m, 1H), 5.72 and 5.83 (2×br. s, 1 H), 7.20 (m, 2H), 7.48 (m, 1H).

Example P34-(4′-Chloro-4-trifluoromethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of4′-chloro-4-trifluoromethyl-biphenyl-3-carbaldehyde

To a mixture of 3-chloro-6-trifluoromethylbenzaldehyde (1.0 g, 4.79mmol), 4-chlorophenyl boronic acid (1.12 g, 7.19 mmol), potassiumphosphate (2.03 g, 9.59 mmol),dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (0.079 g, 0.19mmol) and palladium acetate (0.022 g, 0.096 mmol) is added degassedtoluene (9 ml), then the mixture is further purged with nitrogen. Thesuspension is next sealed then stirred at ambient temperature for 5minutes, than heated at 160° C. for 1 hour under microwave irradiation.After cooling the reaction mixture is partitioned between 2Mhydrochloric acid and dichloromethane, and the aqueous phase furtherextracted with dichloromethane (×2). The organic fractions are combinedthen evaporated under reduced pressure to yield a crude product which ispurified by flash column chromatography (100% hexane to 10% ethylacetate in hexanes as eluant) to afford4′-chloro-4-trifluoromethyl-biphenyl-3-carbaldehyde (1.78 g) as anorange gum. This material is used directly in the next step.

Step 2: Preparation of4-[1-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (0.887g, 6.25 mmoles) in 1,2-dimethoxyethane (10 ml) is added sodium methoxide(0.405 g, 7.50 mmoles) in one portion. The reaction mixture is stirredat 0° C. for 30 minutes, followed by the dropwise addition of4′-chloro-4-trifluoromethylbiphenyl-3-carbaldehyde (1.779 g, 6.25mmoles) as a solution in 1,2-dimethoxyethane (10 ml). The reactionmixture is stirred at 0° C. for 30minutes and then at ambienttemperature for a further 1 hour after which it is partitioned between1M hydrochloric acid and dichloromethane. The aqueous phase is extractedagain with dichloromethane, than all organics are combined andevaporated to afford4-[1-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(2.50 g) as a yellow gum. This material is used directly in the nextstep.

Step 3: Preparation of2-(4′-Chloro-4-trifluoromethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(2.50 g, 6.12 mmol) in methanol (75 ml) at 35 ° C. is added 50% aqueoushydrogen peroxide solution (0.70 ml, 12.2 mmol), followed immediately bya solution of 2M aqueous lithium hydroxide (0.76 ml, 1.52 mmol). Thismixture is stirred at 35° C. for 45 minutes, then allowed to cooled toroom temperature and quenched with saturated sodium metabisulfitesolution. The crude product is extracted with diethyl ether (×2), thenall organics are combined and dried over magnesium sulfate. Afterfiltration the filtrate is concentrated in vacuo to afford2-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(2.59 g) as a yellow gum. This material is used directly in the nextstep.

Step 4: Preparation of4-(4′-Chloro-4-trifluoromethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

To an ice-cold solution of crude2-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(2.59 g, 6.12 mmoles) in dichloroethane (25 ml) is added concentratedsulfuric acid (5 ml), followed by stirring at this temperature for 2hours. The reaction mixture is poured into ice, extracted withdichloromethane (×2), and the combined organics are evaporated underreduced pressure to yield a brown gum. Purification by flash columnchromatography (isohexane to 30% ethyl acetate in isohexane as eluant)then reverse phase preparative HPLC affords4-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione(0.370 g) as a white solid.

1H NMR (CDCl₃): δ7.85 (d, 1H), 7.69 (d, 1H), 7.53 (d, 2H), 7.44 (d, 2H),7.39 (s, 1H), 1.60 (app. d, 6H), 1.48 (s, 6H)

Example P4 Preparation of4-(5-Bromo-2-iodophenyl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of 5-Bromo-2-iodobenzaldehyde

To a solution of 5-bromo-2-iodobenzonitrile (5.00 g, 16.00 mmoles) inanhydrous tetrahydrofuran (80 ml) at −80° C. is added diisobutylaluminium hydride (16.0 ml, 16.0 mmoles, 1M solution in toluene)dropwise over 10 minutes. The reaction mixture is stirred at −80° C. fora 1 hour, then allowed to warm to ambient temperature and stirovernight. Additional diisobutyl aluminium hydride (16.0 ml, 16.0mmoles, 1M solution in toluene) is next added dropwise at roomtemperature, and the reaction mixture further stirred for 1 hour. Aftercareful quenching with 2M hydrochloric acid (cooling in ice bath), thecrude product is extracted with ethyl acetate (×2), then all organicsare combined and dried over magnesium sulfate and filtered. The filtrateis evaporated under reduced pressure then purified by flash columnchromatography (isohexane to 10% ethyl acetate in isohexane eluant) toafford 5-bromo-2-iodobenzaldehyde (0.85 g).

Step 2: Preparation of4-[1-(5-Bromo-2-iodophenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (0.388g, 2.73 mmoles) in anhydrous 1,2-dimethoxyethane (5 ml) is added sodiummethoxide (0.177 g, 3.27 mmoles) in one portion. The reaction mixture isstirred for 5 minutes at this temperature, followed by the dropwiseaddition of 5-bromo-2-iodo-benzaldehyde (0.850 g, 2.73 mmoles) as asolution in 1,2-dimethoxyethane (5 ml). The reaction mixture is furtherstirred at 0° C. for 30 minutes, then at ambient temperature for a 1hour. After partitioning between 1M hydrochloric acid anddichloromethane, the organic phase is separated, and the aqueous phaseis extracted again with additional dichloromethane. All organics arecombined then concentrated in vacuo to afford4-[1-(5-bromo-2-iodophenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(1.18 g) as a yellow gum.

Step 3: Preparation of2-(5-Bromo-2-iodophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(5-bromo-2-iodophenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(1.18 g, 2.73 mmol) in methanol (50 ml) at 35 ° C. is added 50% aqueoushydrogen peroxide solution (0.31 ml, 5.46 mmol), followed immediately by2M aqueous lithium hydroxide (0.34 ml, 0.68 mmol). This mixture isstirred at 35 ° C. for 3 hours, then quenched with saturated aqueoussodium metabisulfite and extracted with dichloromethane. The organicphase is separated, and the aqueous phase extracted again withdichloromethane. All organics are combined then evaporated under reducedpressure to afford2-(5-bromo-2-iodophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-oneas an oil which is used directly in the next step.

Step 4: Preparation of4-(5-Bromo-2-iodophenyl)-2,2,6,6-tetramethylpyran-3,5-dione

To crude2-(5-bromo-2-iodophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(from step 3) is added ice-cold concentrated sulphuric acid, and thereaction mixture is stirred at ambient temperature for 30 minutes. Afterdilution with distilled water the product is extracted withdichloromethane (×2), then the combined organics are evaporated underreduced pressure. Purification by flash column chromatography (20% ethylacetate in isohexane to ethyl acetate as eluant) affords4-(5-bromo-2-iodophenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.225 g) asa beige coloured solid. 1H NMR (CDCl₃): δ7.80 (d, 1H), 7.33 (m, 1H),7.25 (m, 1H), 1.66 (s, 3H), 1.60 (s, 3H), 1.55 (s, 3H), 1.48 (s, 3H).

Example P5 Preparation of4-(5-Bromo-2-trifluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of4-[1-(5-Bromo-2-trifluoromethoxyphenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (2.84g, 20.00 mmol) in anhydrous 1,2-dimethoxyethane (6 ml) is added sodiummethoxide (1.19 g, 22.04 mmol) in one portion. After stirring at thistemperature for 5 minutes a solution of5-bromo-2-trifluoromethoxybenzaldehyde (4.84 g, 18.00 mmol) in1,2-dimethoxyethane (6 ml) is added dropwise over 10mins, followed bystirring at 0° C. for a further 1hour. After warming to room temperaturethe reaction mixture is diluted with ether and washed with 2Mhydrochloric acid (×2). Organic fractions are combined, dried overmagnesium sulphate, filtered and the filtrate evaporated in vacuo toafford4-[1-(5-bromo-2-trifluoromethoxyphenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(7.06 g) as an orange liquid.

Step 2 Preparation of2-(5-Bromo-2-trifluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(5-bromo-2-trifluoromethoxyphenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(7.06 g, 18.00 mmol) in methanol (300 ml) at 35° C. is added 50% aqueoushydrogen peroxide (1.80 ml, 27.00 mmol), immediately followed by 2Maqueous lithium hydroxide (1.80 ml, 3.60 mmol). After stirring at thistemperature for 1 hour the reaction mixture is allowed to cool, thenquenched with 10% sodium metabisulfite solution (negative KI-starchindicator test). The reaction mixture is extracted with diethyl ether(×3), then the organic phase is further washed with saturated aqueoussodium bicarbonate (×2) then brine. All organics are combined, driedover magnesium sulfate, filtered and the filtrate concentrated in vacuoto afford2-(5-bromo-2-trifluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(6.34 g, 86%) as a yellow oil.

1H NMR (CDCl₃): δ 7.84 (s, 0.4H, isomer A), 7.56 (s, 0.6H, isomer B),7.52 (d, 0.6H, isomer B), 7.48 (d, 0.4H, isomer A), 7.15 (d, 0.6H,isomer B), 7.07 (d, 0.4H, isomer A), 4.46 (m, 1H, isomers A and B), 1.47(s, 1.2H, isomer A), 1.39-1.28 (m, 7.8H, isomers A and B), 1.12 (s,1.2H, isomer A), 0.83 (s, 1.8H, isomer B)

Step 3: Preparation of4-(5-Bromo-2-trifluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione

To an ice-cold solution of concentrated sulphuric acid (10 ml) is addeda second solution of2-(5-bromo-2-trifluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(6.34 g, 15.00 mmol) in 1,2-dichloroethane (10 ml) dropwise over 5minutes. This biphasic mixture is stirred vigorously for 2 hours at 0°C., then poured into ice-water, rinsing with a small amount ofadditional 1,2-dichloroethane/water. This mixture is then concentratedunder vacuum to remove all organic solvents, until a free-flowing solidwas produced. The solid is filtered, washed with water then isohexane,followed by drying under vacuum overnight. The solid is next redissolvedin ethyl acetate, dried over magnesium sulfate, filtered and thefiltrate concentrated in vacuo to afford4-(5-bromo-2-trifluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione(4.17 g, 68%).

1H NMR (CDCl₃): δ7.57 (dd, 1H), 7.24 (d, 2H), 1.52 (br.s, 12H).

Example P6 Preparation of4-(4-Bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of 4-Bromo-4′-chloro-biphenyl-3-carbaldehyde

To a solution of 4-bromo-4′-chloro-3-iodobiphenyl (4.80 g, 0.012 mol)(described in WO 2008/071405) in anhydrous diethyl ether/tetrahydrofuran(120 ml, 1:1 ratio) at −75° C. is added isopropyl magnesium bromide(18.96 ml, 15% solution in tetrahydrofuran) dropwise such as to maintainan internal temperature below −70° C. Once addition is complete thereaction mixture is stirred at −75° C. for 2 hours, then warmed to −45°C. Anhydrous N,N-dimethylformamide (1.71 g, 0.0184 mol) is next addeddropwise, maintaining temperature below −40° C., followed by warming toroom temperature and quenching with 2M hydrochloric acid (60 ml). Thereaction mixture is further diluted with diethyl ether, the two phasesseparated, and the aqueous phase extracted with additional diethylether. The combined organic extracts are washed with brine, dried overmagnesium sulfate, filtered and the filtrate concentrated in vacuo. Thecrude product is purified by flash column chromatography (2% ethylacetate in hexane eluant) to afford4-bromo-4′-chloro-biphenyl-3-carbaldehyde (2.7 g, 75%) as a white solid.

Step 2: Preparation of4-[1-(4-Bromo-4′-chlorobiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (1.37g (9.68 mmol) in anhydrous 1,2-dimethoxyethane (10 ml) is added sodiummethoxide (0.575 g, 10.60 mmol) in one portion, followed by stirring atthis temperature for 10 minutes. To this slurry is then added a secondsolution of 4-bromo-4′-chloro-biphenyl-3-carbaldehyde (2.60 g, 8.80mmol) in 1,2-dimethoxyethane (10 ml) dropwise. When addition is completethe reaction mixture is stirred at 0° C. for a further 1 hour, thenquenched with 2M hydrochloric acid (50 ml). After stirring for anadditional 1 hour the solution is diluted with diethyl ether, the twophases separated, and the aqueous phase further extracted with diethylether (×2). The combined organics are further washed with brine, thendried over magnesium sulfate, filtered, and the filtrate concentrated invacuo to afford4-[1-(4-bromo-4′-chlorobiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(3.40 g, 92%) as a yellow gum.

Step 3: Preparation of2-(4-Bromo-4′-chlorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(4-bromo-4′-chlorobiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(3.40 g, 9.03 mmol) in methanol (140 ml) at 35° C. is added 50% aqueoushydrogen peroxide (1.04 ml, 15.60 mmol), immediately followed by 2Maqueous lithium hydroxide (1.15 ml, 2.30 mmol). The reaction mixture isstirred for a further 45 minutes at 35° C., then allowed to cool to roomtemperature and quenched with saturated sodium metabisulfite. Afterextracting the product into diethyl ether (×3) the organic phase isseparated, washed with additional water, then dried over magnesiumsulfate. After filtration the filtrate is concentrated in vacuo toafford2-(4-bromo-4′-chlorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(3.0 g) as a yellow solid. This material was of sufficient purity to usedirectly in the next step.

Step 4: Preparation of4-(4-Bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

To an ice-cold solution of2-(4-bromo-4′-chlorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(3.00 g, 6.90 mmol) in dichloromethane (3.5 ml) is added concentratedsulphuric acid (6.5 ml) at such a rate as maintain an internaltemperature below 5° C. After the addition is completed the reactionmixture is stirred for a further 20 minutes, after which distilled water(25 ml) is added dropwise at 0° C. The reaction mixture is maintained at5-10° C. for 5 minutes, then concentrated in vacuo to remove organicsolvents. The aqueous phase is filtered and the resulting solidtriturated with hexane to afford4-(4-bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione(2.56 g, 85%).

NMR (CDCl₃): δ7.75 (d, 1H), 7.49 (d, 2H), 7.45 (dd, 1H), 7.40 (s, 2H),7.36 (s, 1H), 5.56 (br.s, 1H), 1.65 (s, 3H), 1.58 (s, 3H), 1.53 (s, 3H),1.47 (s, 3H).

Example P7 Preparation of4-(5-Bromo-2-fluorophenyl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of4-[1-(5-Bromo-2-fluorophenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (4.56g, 32.10 mmol) in anhydrous 1,2-dimethoxyethane (25 ml) is added sodiummethoxide (1.91 g, 35.10 mol) in one portion. After stirring at roomtemperature for 10 minutes a second solution of5-bromo-2-fluorobenzaldehyde (5.93 g, 29.10 mmol) in anhydrous1,2-dimethoxyethane (45 ml) is added dropwise, followed by stirring at0° C. for a further 45 minutes. The reaction mixture is quenched with 2Mhydrochloric acid (50 ml), then diluted with diethyl ether and the twophases separated. The aqueous phase is further extracted with diethylether (×2), then all organics are combined, washed with brine and driedover magnesium sulfate. After filtration the filtrate is concentrated invacuo to afford4-[1-(5-bromo-2-fluorophenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(9.30 g, 96%) as a yellow gum.

Step 2: Preparation of2-(5-Bromo-2-fluorophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(5-bromo-2-fluorophenyl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(9.30 g, 29.00 mmol) in methanol (280 ml) at 35° C. is added 50% aqueoushydrogen peroxide (3.36 ml, 50.40 mmol), followed immediately by 2Maqueous lithium hydroxide (3.68 ml, 7.36 mmol). Stirring is continued atthis temperature for 1 hour, then the reaction mixture is allowed tocool to room temperature, then quenched with saturated sodiummetabisulfite (100 ml) and extracted with ether (×3). Organics arecombined, dried over magnesium sulfate, then filtered and the filtrateconcentrated in vacuo to afford2-(5-bromo-2-fluorophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(6.60 g, 68%) as a yellow gum.

Step 3: Preparation of4-(5-Bromo-2-fluorophenyl)-2,2,6,6-tetramethylpyran-3,5-dione

To a solution of2-(5-bromo-2-fluorophenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(6.60 g, 19.30 mmol) in dichloromethane (8 ml) is added a secondice-cold solution of concentrated sulphuric acid (13.8 ml) dropwise,maintaining temperature below 5° C. The reaction mixture is stirred fora further 30 minutes, then quenched with distilled water (50 ml). Afterstirring for an additional 10 minutes the organics are removed in vacuo,and the resulting precipitate is filtered then triturated with water.After washing with hexanes the solid is dried to afford4-(5-bromo-2-fluorophenyl)-2,2,6,6-tetramethylpyran-3,5-dione (4.30 g,65%).

1H NMR (CDCl₃): δ7.5 (m, 1H), 7.34 (m, 1H), 7.06 (m, 1H), 5.69 (br. s,1H), 1.56 (d, 6H), 1.52 (d, 6H).

Example P8 Preparation of4-(4′-Chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of4′-chloro-2′-fluoro-4-hydroxybiphenyl-3-carbaldehyde

To a mixture of 5-bromosalicyaldehyde (30.0 g, 0.15 mol),2-fluoro-4-chlorophenylboronic acid (30.0 g, 0.17 mol) and sodiumcarbonate (24.0 g, 0.23 mol) is added 1,2-dimethoxyethane (225 ml) anddistilled water (75 ml), and the suspension is stirred under a nitrogenatmosphere. To this mixture is then added[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (4.5 g, 7.5mmol), followed by heating at reflux overnight. After cooling to roomtemperature and dilution with distilled water (500 ml) anddichloromethane (500 ml), the two phases are separated, and the aqueousphase extracted again with dichloromethane (2×500 ml). Organic fractionsare combined, washed with brine (800 ml) then dried over magnesiumsulphate. The suspension is filtered and the filtrate is concentrated invacuo. Then crude material is purified by flash column purification(5-10% ethyl acetate in isohexane eluant) to afford4′-chloro-2′-fluoro-4-hydroxybiphenyl-3-carbaldehyde (33.61 g, 89%) as apale yellow solid.

Step 2: Preparation of Trifluoromethanesulfonic acid4′-chloro-2′-fluoro-3-formylbiphenyl-4-yl ester

To an ice-cold mixture of4′-chloro-2′-fluoro-4-hydroxybiphenyl-3-carbaldehyde (33.60 g, 0.13 mol)and pyridine (31.0 ml, 0.36 mol) in anhydrous dichloromethane (700 ml)is added triflic anhydride (27.0 ml, 0.16 mmol) dropwise over 30minutes, maintaining temperature below 10° C. The reaction mixture isthen allowed to warm to room temperature, followed by stirringovernight. After dilution with distilled water (500 ml) anddichloromethane (500 ml), the two layers are separated and the aqueousphase is extracted again with dichloromethane (2×500 ml). Organicfractions are combined, washed with brine (800 ml), then dried overmagnesium sulfate and concentrated in vacuo. The crude product ispurified by flash column chromatography (10% ethyl acetate in hexaneeluant) to afford trifluoromethanesulfonic acid4′-chloro-2′-fluoro-3-formylbiphenyl-4-yl ester as a yellow oil.

Step 3: Preparation of4′-Chloro-4-cyclopropyl-2′-fluorobiphenyl-3-carbaldehyde

To a mixture of trifluoromethanesulfonic acid4′-chloro-2′-fluoro-3-formylbiphenyl-4-yl ester (30.0 g, 0.078 mol),cyclopropyl boronic acid (8.80 g, 0.10 mol), potassium phosphate (58.40g, 0.28 mol) and sodium bromide (8.0 g, 0.078 mol) is added toluene (300ml) then distilled water (30 ml) under a nitrogen atmosphere. To thismixture is then added tetrakis(triphenylphosphine) palladium (9.60 g,8.40 mmol) in one portion, and the mixture is then heated at 100° C.overnight. After cooling to room temperature the mixture is diluted withdistilled water (500 ml) and ethyl acetate (500 ml), and the two layersare separated and the aqueous phase extracted again with ethyl acetate(2×500 ml). Organic fractions are combined, washed with distilled water(1 L) then brine (1 L), and then dried over magnesium sulphate. Thesuspension is filtered and the filtrate concentrated in vacuo. The crudeproduct is purified by flash column chromatography on silica gel, thenadditionally by flash column chromatography on basic alumina (10% ethylacetate in hexane as eluant) to afford4′-chloro-4-cyclopropyl-2′-fluoro-biphenyl-3-carbaldehyde (7.6 g, 36%).

Step 4:4-[1-(4′-Chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (8.40g, 0.059 mol) in anhydrous 1,2-dimethoxyethane (75 ml) is added sodiummethoxide (3.60 g, 0.066 mol) in one portion, and the mixture is stirredat this temperature for 30 minutes. A solution of4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-carbaldehyde (14.80 g, 0.054mmol) is then added dropwise over 20 minutes, maintaining temperaturebelow 10° C. The reaction mixture is stirred at this temperature for 1hour, then allowed to warm to room temperature before diluting withdiethyl ether and distilled water. The two phases are separated, and theaqueous phase is extracted again with diethyl ether (×2). Organicfractions are combined, washed with brine, then dried over magnesiumsulfate. The suspension is filtered and the filtrate concentrated invacuo to afford4-[1-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(19.80 g) which is of sufficient purity to use directly in the nextstep.

Step 5:2-(4′-Chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one

To a solution of4-[1-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(19.80 g, 0.050 mol) in methanol (830 ml) at 35° C. is added 50% aqueoushydrogen peroxide (5.00 ml, 0.075 mmol), followed immediately by 2Mlithium hydroxide (5.00 ml, 0.01 mol) solution. The mixture is stirredat this temperature for a further 2 hours, then allowed to cool to roomtemperature. Then reaction mixture is quenched with 10% sodiummetabisulfite (negative KI-starch indicator test) then diluted withdiethyl ether. Most of the methanol is removed under vacuum, and thecrude mixture is partitioned between distilled water and diethyl ether.The aqueous phase is further extracted with diethyl ether (×2), then allorganics are combined and washed with saturated sodium bicarbonate (×2)then brine. After anhydrousing over magnesium sulfate the suspension isfiltered and the filtrate concentrated in vacuo to afford2-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one(18.2 g) as an orange foam. This material is of sufficient purity to usedirectly in the next step without further purification.

1H NMR (CDCl₃): δ 7.48 (s, 1H), 7.39 (d, 1H), 7.32 (t, 1H), 7.24-7.12(m, 2H), 7.00 (d, 1H), 4.76 (s, 1H), 1.84-1.76 (m, 1H), 1.42-1.26 (m,9H), 1.11-0.96 (m, 2H), 0.88-0.79 (m, 4H), 0.78-0.71(m, 1H).

Step 6: Preparation of4-(4′-Chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

To a mixture of2-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(18.20 g, 0.044 mol) and ytterbium triflate (2.40 g, 4.40 mmol) is addeda solution of 5M lithium perchlorate (prepared from 46 ml diethyl etherand 24.40 g lithium perchlorate). The resulting suspension is stirred atroom temperature for 3 days, then is diluted with diethyl ether (85 ml)and additional ytterbium triflate (7.80 g, 0.014 mol) is added. Afterstirring at room temperature for a further 3 days additional ytterbiumtriflate (13.63 g, 0.025 mol) is added, and the reaction mixture isstirred for 11 days. Finally, extra lithium perchlorate (24.40 g, 0.23mol) is added in one portion, and the mixture is heated at 27° C.(internal temperature) for 1 day. The reaction mixture is partitionedbetween diethyl ether and distilled water, the two phases separated, andthe aqueous phase is extracted with diethyl ether (×2). The organicfractions are combined, washed with brine then dried over magnesiumsulphate. The suspension is filtered and the filtrate concentrated invacuo. The crude material purified by flash column chromatography (10%ethyl acetate in hexanes as eluant) to afford an oil which is trituratedwith hexanes to afford4-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione(4.78 g) as a white solid.

1H NMR (CDCl₃): δ 7.47 (d, 1H), 7.38 (t, 1H), 7.23 (s, 1H), 7.21-7.12(m, 3H), 5.68 (s, 1H), 1.75 (m, 1H), 1.62 (s, 6H), 1.49 (s, 6H),0.92-0.82 (m, 2H), 0.81-0.75 (m, 1H), 0.61-0.53 (m, 1H)

Example P9 Preparation of4-(2′,4′-Dichloro-4-cyclopropylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of 2′,4′-Dichloro-4-hydroxybiphenyl-3-carbaldehyde

To a mixture of 5-bromosalicyaldehyde (30.0 g, 0.15 mol),2,4-dichlorophenylboronic acid (32.0 g, 0.17 mol) and sodium carbonate(24.0 g, 0.23 mol) is added 1,2-dimethoxyethane (225 ml) and distilledwater (75 ml), and the suspension is stirred under a nitrogenatmosphere. To this mixture is then added[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (4.5 g, 7.5mmol), followed by heating at reflux overnight. After cooling to roomtemperature and dilution with distilled water (500 ml) anddichloromethane (500 ml), the two phases are separated, and the aqueousphase extracted again with dichloromethane (2×500 ml). Organic fractionsare combined, washed with brine (800 ml) then dried over magnesiumsulphate. The suspension is filtered and the filtrate concentrated invacuo. Then crude material is finally purified by flash columnpurification (10% ethyl acetate in isohexane eluant) to afford2′,4′-dichloro-4-hydroxybiphenyl-3-carbaldehyde (32.73 g, 82%) as a paleyellow solid.

Step 2: Preparation of Trifluoromethanesulfonic acid2′,4′-dichloro-3-formylbiphenyl-4-yl ester

To an ice-cold mixture of2′,4′-dichloro-4-hydroxybiphenyl-3-carbaldehyde (31.70 g, 0.12 mol) andpyridine (25.0 ml, 0.29 mol) in anhydrous dichloromethane (650 ml) isadded triflic anhydride (22.0 ml, 0.13 mmol) dropwise over 30 minutes,maintaining temperature between 0-10° C. The reaction mixture is thenallowed to warm to room temperature, followed by stirring overnight.After dilution with distilled water (500 ml) and dichloromethane (300ml), the two layers are separated and the organic phase is furtherwashed with saturated aqueous copper sulfate solution (3×500 ml), water(500 ml), then brine (500 ml). After anhydrousing over magnesium sulfatethe solvent is removed under vacuum and the crude product is purified byflash column chromatography (10% ethyl acetate in hexane eluant) toafford trifluoromethanesulfonic acid2′,4′-dichloro-3-formylbiphenyl-4-yl ester as an orange oil.

Step 3: Preparation of2′,4′-Dichloro-4-cyclopropylbiphenyl-3-carbaldehyde

To a mixture of trifluoromethanesulfonic acid2′,4′-dichloro-3-formylbiphenyl-4-yl ester (30.0 g, 0.075 mol),cyclopropyl boronic acid (8.50 g, 0.097 mol), potassium phosphate (56.30g, 0.27 mol) and sodium bromide (7.7 g, 0.075 mol) is added toluene (300ml) then distilled water (30 ml) under a nitrogen atmosphere. To thismixture is then added tetrakis(triphenylphosphine) palladium (9.30 g,0.0081 mol) in one portion, and the mixture is then heated at 100° C.overnight. After cooling to room temperature the mixture is diluted withdistilled water (500 ml) and ethyl acetate (500 ml), and the two layersare separated. The aqueous phase is extracted again with ethyl acetate(2×500 ml), then all organic fractions are combined, then washed withdistilled water (1L) then brine (1L). After drying over magnesiumsulfate the suspension is filtered and the filtrate is concentrated invacuo. The crude product is purified by flash column chromatography onsilica gel (2-10% ethyl acetate in hexanes as eluant), then additionallyby flash column chromatography on basic alumina (10% ethyl acetate inhexane as eluant) to afford2′,4′-dichloro-4-cyclopropylbiphenyl-3-carbaldehyde (11.7 g, 54%).

Step 4:4-[1-(2′,4′-Dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (15.70g, 0.11 mol) in anhydrous 1,2-dimethoxyethane (285 ml) is added sodiummethoxide (6.50 g, 0.12 mol) in one portion, and the mixture is stirredat this temperature for 30 minutes. A solution of2′,4′-dichloro-4-cyclopropylbiphenyl-3-carbaldehyde (13.70 g, 0.047mmol) is then added dropwise over 20 minutes, maintaining temperaturebelow 10° C. The reaction mixture is stirred at this temperature for 2hours, then allowed to warm to room temperature before diluting withdiethyl ether and distilled water. The two phases are separated, and theaqueous phase is extracted again with diethyl ether (×2). Organicfractions are combined, washed with brine, then dried over magnesiumsulphate. The suspension is filtered and filtrate concentrated in vacuo.The aqueous phase is further acidified with 2M hydrochloric acid thenextracted again with diethyl ether (×2), dried over magnesium sulfateand concentrated in vacuo. All organics are combined, then diluted withtoluene and azeotroped (×4) to afford4-[1-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(20.0 g) which is of sufficient purity to use directly in the next step.

Step 5:2-(2′,4′-Dichloro-4-cyclopropylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one

To a solution of4-[1-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(20.0 g, 0.048 mol) in methanol (800 ml) at 35° C. is added 50% aqueoushydrogen peroxide (4.80 ml, 0.072 mmol), followed immediately by 2Mlithium hydroxide (4.80 ml, 9.60 mmol) solution. The mixture is stirredat this temperature for a further 2 hours, then allowed to cool to roomtemperature. Then reaction mixture is quenched with 10% sodiummetabisulfite (negative KI-starch indicator test) then diluted withdiethyl ether. Most of the methanol is removed under vacuum, and thecrude mixture is partitioned between distilled water and diethyl ether.The aqueous phase is further extracted with diethyl ether (×2), then allorganics are combined and washed with saturated sodium bicarbonate (×2)then brine. After drying over magnesium sulfate the suspension isfiltered and the filtrate concentrated in vacuo to afford2-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one(17.80 g) as an orange foam. This material is of sufficient purity touse directly in the next step without further purification.

1H NMR (CDCl₃): δ 7.49 (s, 1H), 7.37 (s, 1H), 7.37-7.25 (m, 2H), 7.20(d, 1H), 6.99 (d, 1H), 4.75 (s, 1H), 1.80 (m, 1H), 1.40-1.28 (m, 9H),1.10-0.98 (m, 2H), 0.90-0.80 (m, 4H), 0.75-0.80 (m, 1H).

Step 6: Preparation of4-(2′,4′-Dichloro-4-cyclopropylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

To a mixture of2-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one(17.80 g, 0.041 mol) and ytterbium triflate (2.20 g, 4.41 mmol) is addeda solution of 5M lithium perchlorate (prepared from 42 ml diethyl etherand 22.30 g lithium perchlorate). The resulting suspension is stirred atroom temperature for 17 days, at which stage further diethyl ether (42ml), lithium perchlorate (22.3 g, 0.21 mol) and ytterbium triflate (19.8g, 0.035 mol) is added. The reaction mixture is then heated at 27° C.(internal temperature) for 1 day, followed by partitioning betweendiethyl ether and distilled water. The two phases are separated, theaqueous phase is extracted with diethyl ether (×2), and then all organicfractions are combined, washed with brine then dried over magnesiumsulphate. The suspension is filtered and the filtrate is concentrated invacuo. The crude material is purified by flash column chromatography(ethyl acetate/hexane eluant) to give an oil which is triturated withhexanes to afford4-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione(2.80 g) as a white solid.

1H NMR (CDCl₃): δ 7.48 (s, 1H), 7.38 (dd, 1H), 7.29 (s, 2H), 7.16-7.11(m, 2H), 5.69 (s, 1H), 1.76 (m, 1H), 1.61 (d, 6H), 1.49 (d, 6H),0.92-0.86 (m, 2H), 0.82-0.76 (m, 1H), 0.62-0.54 (m, 1H).

Example P10 Preparation of4-(2′,4′-Dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of 2′,4′-Dichloro-4-ethylbiphenyl-3-carbaldehyde

A suspension of 5-bromo-2-ethylbenzaldehyde (1.0 g, 4.7 mmol),2,4-dichlorophenyl boronic acid (1.34 g, 7.0 mmol) and sodium carbonate(0.99 g, 7.98 mmol) in a mixed solvent system of 1,2-dimethoxyethane (12ml) and distilled water (4 ml) is stirred under a nitrogen atmosphere,then flushed with nitrogen (×2). [1,140-Bis(diphenylphosphino)ferrocene]palladium(II)chloride (1.15 g, 1.41mmol) is then added in one portion and the suspension is again flushedwith nitrogen, then heated at reflux overnight. After cooling to roomtemperature the reaction mixture is diluted with distilled water (10 ml)and extracted with dichloromethane (10 ml). The aqueous phase isextracted again with dichloromethane (×2), and the combined organicfractions are finally washed with brine then dried over magnesiumsulfate. The crude product is purified by flash column chromatography(isohexane to 75:25 isohexane/ethyl acetate ratio eluant) to afford2′,4′-dichloro-4-ethylbiphenyl-3-carbaldehyde as a yellow oil.

Step 2: Preparation of4-[1-(2′,4′-Dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (1.15g, 0.0081 mol) in 1,2-dimethoxyethane (2 ml) is added sodium methoxide(0.481 g, 0.0089 mol) in one portion. The reaction mixture is thenstirred for 5 minutes at this temperature, followed by the addition of asecond solution of 2′,4′-dichloro-4-ethylbiphenyl-3-carbaldehyde (2.02g, 0.0072 mol) in 1,2-dimethoxyethane (2.7 ml). After stirring for anadditional 2 hours at 0° C. the reaction mixture is allowed to stand atroom temperature overnight. The crude solution is poured into 2Mhydrochloric acid and extracted with ether (×3). The organics arecombined, washed with brine, dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by flash columnchromatography (5% ethyl acetate in isohexane to 25% ethyl acetate inisohexane) to afford4-[1-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-oneas a yellow gum.

Step 3A: Preparation of2-(2′,4′-Dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(2.04 g, 0.0051 mol) in methanol (24 ml) at 55° C. is added hydrogenperoxide solution (0.43 ml, 0.0076 mmol, 50% wt solution), followedimmediately by aqueous lithium hydroxide (0.25 ml, 0.0005 mol). Thereaction mixture is heated at this temperature for 30 minutes, then israpidly cooled to room temperature and quenched with saturated sodiumthiosulphate. The crude product is extracted with diethyl ether (×3),washed with saturated sodium bicarbonate, then dried over magnesiumsulfate. The residue is purified by flash column chromatography (5%ethyl acetate in isohexane to 25% ethyl acetate in isohexane) to afford2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-oneas a yellow gum.

Step 3B: Preparation of2-(2′,4′-Dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(0.500 g, 1.24 mmol) in toluene (3.7 ml) is added aqueous sodiumhyperchlorite solution (3.30 g, 6.20 mmol, 14% active chlorine) andtetrabutylammonium hydrogen sulfate (0.013 g, 0.04 mmol), and thebiphasic mixture is then stirred at 50° C. for 4 hours. The reactionmixture is then dilluted with additional toluene, the phases separated,and the organic phase washed again with distilled water (×2). Theorganic phase is dried over sodium sulfate then concentrated in vacuo toafford2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-oneas a white solid.

Step 4A: Preparation of4-(2′,4′-Dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

To an ice-cold solution of concentrated sulphuric acid (6 ml) is added asecond solution of 2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4 ,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (1.90 g, 0.0045 mol) in1,2-dichloroethane (6 ml) dropwise over 5 mins. This biphasic mixture isstirred vigorously for 2 hours at 0° C., then is poured into ice andextracted with diethyl ether. All organics are combined, washed withbrine, dried over magnesium sulfate then concentrated in vacuo. Thecrude product is purified by flash column chromatography (5% ethylacetate in isohexane to 25% ethyl acetate in isohexane) to afford4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dioneas a yellow gum.

1H NMR (CDCl₃): δ 7.48 (d, 1H), 7.43 (m, 2H), 7.30 (m, 2H), 7.13 (d,1H), 5.71 (br. s, 1H), 2.55-2.44 (m, 2H), 1.62 (s, 6H), 1.49 (app. d,6H), 1.17 (t, 3H).

Step 4B: Preparation of4-(2′,4′-Dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione

To a solution of2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(0.0418 g, 0.10 mmol) in toluene (0.3 ml) is added p-toluenesulfonicacid monohydrate (0.019 g, 0.10 mmol). The mixture is then heated at150° C. for 1hour, after which it is allowed to cool to roomtemperature. The reaction mixture is poured into distilled water, driedover sodium sulfate, then concentrated in vacuo to afford4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione.

Example P11 Preparation of4-(5-Bromo-2-difluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione

Step 1: Preparation of 5-Bromo-2-difluoromethoxybenzaldehyde

To a suspension of 5-bromosalicylaldehyde (7.60 g, 0.038 mol) and cesiumcarbonate (17.30 g, 0.053 mol) in anhydrous N,N-dimethylformamide (55ml) is added sodium chlorodifluoroacetate (13.30 g, 0.087 mol) followedby distilled water (10 ml). The reaction mixture is heated at 100° C.for 6 hours (large pieces of solid are broken-up with a spatula), thenallowed to cool to room temperature and is quenched with concentratedhydrochloric acid (15 ml). After stirring for a further 2 hours thereaction mixture is diluted with distilled water and extracted withethyl acetate (×2). Organic fractions are combined, washed with 2Maqueous sodium hydroxide, brine, then dried over magnesium sulfate. Thesuspension is filtered and the filtrate concentrated in vacuo to afford5-bromo-2-trifluoromethoxybenzaldehyde (5.66 g) of sufficient purity touse directly in the next step.

Step 2: Preparation of4-[1-(5-Bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one

To an ice-cold solution of 2,2,5,5-tetramethyldihydrofuran-3-one (3.60g, 0.025 mol) in anhydrous 1,2-dimethoxyethane (8 ml) is added sodiummethoxide (1.51 g, 0.028 mol) in one portion. After stirring at thistemperature for 5 minutes a solution of5-bromo-2-difluoromethoxy-benzaldehyde (5.66 g, 0.023 mol) in1,2-dimethoxyethane (8 ml) is added dropwise over 10 mins, followed bystirring at 0° C. for a further 1 hour. After warming to roomtemperature the reaction mixture is diluted with ether and washed with2M hydrochloric acid (×2). Organic fractions are combined, dried overmagnesium sulfate and evaporated in vacuo to afford4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(8.89 g) as an orange oil.

Step 3: Preparation of2-(5-Bromo-2-difluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one

To a solution of4-[1-(5-bromo-2-difluoromethoxyphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one(8.89 g, 0.023 mol) in methanol (380 ml) at 35° C. is added 50% aqueoushydrogen peroxide (2.30 ml, 0.034 mol), immediately followed by 2Maqueous lithium hydroxide (2.30 ml, 0.0046 mmol). After stirring at thistemperature for 1 hour the reaction mixture is allowed to cool, thenquenched with 10% sodium metabisulfite solution (negative KI-starchindicator test). The reaction mixture is extracted with diethyl ether(×3), then the organic phase is further washed with saturated aqueoussodium bicarbonate (×2) then brine. All organics are combined, driedover magnesium sulfate, filtered and the filtrate concentrated in vacuoto afford2-(5-bromo-2-difluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(7.22 g) a yellow gum.

Step 4: Preparation of4-(5-Bromo-2-difluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione

To an ice-cold solution of concentrated sulphuric acid (12 ml) is addeda second solution of2-(5-bromo-2-difluoromethoxyphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one(7.22 g, 18.00 mmol) in 1,2-dichloroethane (12 ml) dropwise over 5minutes. This biphasic mixture is stirred vigorously for 2 hours at 0°C., then allowed to stand at room temperature overnight. The reactionmixture is poured into ice-water, rinsing with a small amount ofadditional 1,2-dichloroethane/water, then concentrated under vacuum toremove all organic solvents. The crude product is next extracted intoethyl acetate (×3), than all organics are combined, washed with brine,and dried over magnesium sulfate. The suspension is filtered and thefiltrate is concentrated in vacuo then purified by flash columnchromatography (10% to 25% ethyl acetate in hexane as eluant) to give anoil which is triturated with hexanes to afford4-(5-bromo-2-difluoromethoxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione(2.08 g) as a white solid.

1H NMR (CDCl₃): δ 7.54 (dd, 0.75H, isomer A), 7.51 (dd, 0.25H, isomerB), 7.37 (d, 0.75H, isomer A), 7.32 (d, 0.25H, isomer B), 7.15 (d,0.75H, isomer A), 7.06 (d, 0.25H, isomer), 6.32 (t, 0.75H, isomer A),6.29 (t, 0.25H, isomer B) 1H), 5.86 (s, 0.75H, isomer A), 5.28 (s,0.25H, isomer A), 1.58-1.44 (m, 12H, isomers A and B).

1. Compounds of formula I

wherein R¹ is halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₃-C₆cycloalkyl,C₁-C₄alkoxy, C₁-C₄haloalkoxy, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl,C₁-C₄alkylsulfonyl, R² is hydrogen, halogen, methylsulfonyloxy,C₁-C₄haloalkylsulfonyloxy, p-tolylsulfonyloxy, optionally substitutedaryl or optionally substituted heteroaryl; r is 0, 1, 2 or 3; R³, if ris 1, is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, cyano or nitro;or the substituents R³, if r is 2 or 3, independently of each other, areC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, cyano or nitro;Y is O, S, SO, SO₂ or CO, R⁴, R⁵, R⁶ and R⁷, independently of eachother, are hydrogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxyC₁-C₄alkyl,C₁-C₄alkylthioC₁-C₄alkyl, C₁-C₄alkylsulfinylC₁-C₄alkyl,C₁-C₄alkylsulfonylC₁-C₄alkyl, cyclopropyl or cyclopropyl substituted byC₁- or C₂alkyl, C₁- or C₂haloalkyl or halogen; cyclobutyl or cyclobutylsubstituted by C₁- or C₂alkyl; oxetanyl or oxetanyl substituted by C₁-or C₂alkyl; C₅-C₇cycloalkyl or C₅-C₇cycloalkyl substituted by C₁- orC₂alkyl or C₁- or C₂haloalkyl, where a methylene group of the cycloalkylmoiety is optionally replaced by an oxygen or sulfur atom or a sulfinylor sulfonyl group; C₄-C₇cycloalkenyl or C₄-C₇cycloalkenyl substituted byC₁- or C₂alkyl or C₁- or C₂haloalkyl, where a methylene group of thecycloalkenyl moiety is optionally replaced by an oxygen or sulfur atomor a sulfinyl or sulfonyl group; cyclopropylC₁-C₅alkyl orcyclopropylC₁-C₅alkyl substituted by C₁- or C₂alkyl, C₁- or C₂haloalkylor halogen; cyclobutylC₁-C₅alkyl or cyclobutylC₁-C₅alkyl substituted byC₁- or C₂alkyl; oxetanylC₁-C₅alkyl or oxetanylC₁-C₅alkyl substituted byC₁- or C₂alkyl; C₅-C₇ cycloalkylC₁-C₅alkyl or C₅-C₇cycloalkylC₁-C₅alkylsubstituted by C₁-or C₂alkyl or C₁- or C₂haloalkyl, where a methylenegroup of the cycloalkyl moiety is optionally replaced by an oxygen orsulfur atom or a sulfinyl or sulfonyl group; C₄-C₇cycloalkenylC₁-C₅alkyl or C₄-C₇cycloalkenylC₁-C₅alkyl which is substituted by C₁- orC₂alkyl or C₁- or C₂haloalkyl, where a methylene group of thecycloalkenyl moiety is optionally replaced by an oxygen or sulfur atomor a sulfinyl or sulfonyl group; phenyl or phenyl substituted byC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl, halogen, nitro, cyano,C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl orC₁-C₄alkylcarbonyl; benzyl or benzyl substituted by C₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄haloalkyl, halogen, nitro, cyano, C₁-C₄alkylthio,C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl or C₁-C₄alkylcarbonyl; heteroarylor heteroaryl substituted by C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,halogen, nitro, cyano, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl,C₁-C₄alkylsulfonyl or C₁-C₄alkylcarbonyl; or R⁴ and R⁵, or R⁶ and R⁷,are joined to form a 5-7 membered saturated or unsaturated ring in whicha methylene group is optionally replaced by an oxygen or sulfur atom, ora 5-7 membered saturated or unsaturated ring substituted by C₁- orC₂alkyl, where a methylene group of the ring is optionally replaced byan oxygen or sulfur atom; or R⁴ and R⁷ are joined to form a 5-7 memberedsaturated or unsaturated ring unsubstituted or substituted by C₁- orC₂alkyl, C₁- or C₂alkoxy, C,-or C₂alkoxyC₁- or C₂alkyl, hydroxy,halogen, phenyl or phenyl substituted by C₁-C₄alkyl, C₁-C₄alkoxy,C₁-C₄haloalkyl, halogen, nitro, cyano, C₁-C₄alkylthio,C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl or C₁-C₄alkylcarbonyl; heteroarylor heteroaryl substituted by C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄haloalkyl,halogen, nitro, cyano, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl,C₁-C₄alkylsulfonyl or C₁-C₄alkylcarbonyl.
 2. A compound according toclaim 1, wherein R¹ is halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₃-C₆cycloalkyl or C₁-C₄-haloalkoxy.
 3. A compound according to claim 1,wherein R² is halogen, aryl or heteroaryl; or aryl or heteroaryl bothsubstituted by halogen, C₁-C₄alkyl, C₁-C₄haloalkyl, C₂-C₄alkenyl,C₂-C₄haloalkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄haloalkoxy, phenoxy,C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl,C₁-C₄haloalkylthio, C₁-C₄haloalkylsulfinyl, C₁-C₄haloalkylsulfonyl,C₃-C₆cycloalkyl, C₁-C₄alkylsulfonyloxy, C₁-C₄haloalkylsulfonyloxy,C₁-C₄alkoxyC₁-C₄alkyl, C₁-C₄alkylthioC₁-C₄alkyl,C₁-C₄alkylsulfinylC₁-C₄alkyl, C₁-C₄alkylsulfonylC₁-C₄alkyl, nitro,cyano, thiocyanato, hydroxy, amino, C₁-C₆alkylamino, C₁-C₆dialkylamino,C₃-C₆cycloalkylamino, morpholino, thiomorpholino,C₁-C₆alkylcarbonylamino, C₁-C₆alkoxycarbonylamino, C₃-C₆alkenyloxycarbonylamino, C₃-C₆ alkynyloxycarbonylamino, C₁-C₆alkylaminocarbonylamino, di(C₁₋₆alkyl)aminocarbonylamino, formyl,C₁-C₆alkyl-carbonyl, C₂-C₆alkenylcarbonyl, C₂-C₆alkynylcarbonyl,carboxy, C₁-C₆alkoxycarbonyl, C₃-C₆alkenyloxycarbonyl,C₃-C₆alkynyloxycarbonyl, carboxamido, C₁-C₆alkylaminocarbonyl,di(C₁-C₆alkyl)aminocarbonyl, C₁-C₆alkylcarbonyloxy,C₁-C₆alkylaminocarbonyloxy, di(C₁-C₆alkyl)aminocarbonyloxy orC₁-C₆alkylthiocarbonylamino.
 4. A compound according to claim 3, whereinR² in the compounds of formula I is halogen, aryl or heteroaryl; or arylor heteroaryl both substituted by halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,phenoxy, C₂-C₄alkenyl, C₂-C₄haloalkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, C₁-C₄alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl,C₁-C₄haloalkylthio, C₁-C₄haloalkylsulfinyl, C₁-C₄haloalkylsulfonyl,nitro or cyano.
 5. A compound according to claim 4, wherein R² isphenyl, thienyl, furyl, pyrrolyl, isoxazolyl, oxazolyl, isothiazolyl,thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl,pyrimidinyl, pyrazinyl, triazinyl, pyridazinyl, oxadiazolyl andthiadiazolyl, and N-oxides and salts thereof, where these rings areunsubstituted or substituted by halogen, C₁-C₄alkyl, C₁-C₄haloalkyl,C₂-C₄alkenyl, C₂-C₄haloalkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,C₁-C₄haloalkoxy, C₁-C₄alkylthio,C₁-C₄alkylsulfinyl, C₁-C₄alkylsulfonyl,C₁-C₄haloalkylthio, C₁-C₄haloalkylsulfinyl,C₁-C₄haloalkylsulfonyl, nitroor cyano.
 6. A compound according to claim 5, wherein R² is phenyl orpyridyl or phenyl or pyridyl, both substituted by halogen, nitro, cyano,C₁-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂alkoxy or C₁-C₂haloalkoxy.
 7. Acompound according to claim 6, wherein R² is phenyl substituted at thepara-position by halogen and is optionally further substituted byhalogen, nitro, C₁-C₂alkyl, C₁-C₂haloalkyl, C₁-C₂alkoxy orC₁-C₂haloalkoxy.
 8. A compound according to claim 1, wherein R³ ishydrogen or C₁-C₆alkyl.
 9. A compound according to claim 1, wherein R³,if r is 1, is C₁-C₃alkyl.
 10. A compound according to claim 1, whereinR⁴, R⁵, R⁶ and R⁷, independently of each other, are hydrogen,C₁-C₄alkyl, C₁-C₄haloalkyl, C₁-C₄alkoxyC₁-C₄ alkyl,C₁-C₄alkylthioC₁-C₄alkyl, C₁-C₄alkylsulfinylC₁-C₄alkyl,C₁-C₄alkylsulfonylC₁-C₄alkyl; C₅-C₇cycloalkyl or C₅-C₇cycloalkylsubstituted by C₁- or C₂alkyl or C₁- or C₂haloalkyl and in which amethylene group is optionally replaced by an oxygen or sulfur atom or asulfinyl or sulfonyl group; C₅-C₇cycloalkylC₁-C₅alkyl orC₅-C₇cycloalkylC₁-C₅alkyl substituted by C₁-C₂alkyl or C₁- orC₂haloalkyl and in which a methylene group is optionally replaced by anoxygen or sulfur atom or a sulfinyl or sulfonyl group.
 11. A compoundaccording to claim 10, wherein R⁴, R⁵, R⁶ and R⁷, independently of eachother, are hydrogen, C₁-C₂alkyl, C₁-C₂haloalkyl orC₁-C₂alkoxyC₁-C₂alkyl.
 12. A compound according to claim 1, wherein Y isO.
 13. A compound according to claim 1, wherein R¹ is ethyl, methyl orcyclopropyl, R² is phenyl or phenyl substituted by halogen orC₁-C₂alkyl, R³ is hydrogen, R⁴, R⁵, R⁶ and R⁷, independently of eachother, are C₁-C₂alkyl, and Y is O.
 14. A process for the preparation ofa compound of formula I

wherein R¹ to R⁷ and n are as defined in claim 1, which comprisesreacting a compound of formula (F)

with a compound of formula (D)


15. A process for the preparation of a compound of formula I

wherein R¹ to R⁷ and n are as defined in claim 1, which comprisesreacting a compound of formula (C)

with a compound of formula (D)

to give a compound of formula (B)

and further reaction with an oxidizing agent.
 16. A process for thepreparation of a compound of formula (A)

which comprises reacting a compound of formula (I)

with an acid.